Counterfactual MRI Generation with Denoising Diffusion Models for Interpretable Alzheimer’s Disease Effect Detection

Generative AI models have recently achieved mainstream attention with the advent of powerful approaches such as SORA, DALL-E and stable diffusion. The underlying breakthrough generative mechanism of denoising diffusion modeling can generate high quality synthetic images and can learn the underlying distribution of complex, high-dimensional data. In our paper, we train conditional latent diffusion models (LDM) and denoising diffusion probabilistic models (DDPM) to provide insight into Alzheimer’s disease (AD) effects on the brain’s anatomy at the individual level. We first created diffusion models that could generate synthetic MRIs, by training them on real 3D T1-weighted MRI scans, and conditioning the generative process on the clinical diagnosis as a context variable. We conducted experiments to overcome limitations in training dataset size, compute time and memory resources by testing different models, effects of pretraining, training duration. We tested the sampling quality of the disease-conditioned diffusion using metrics to assess realism and diversity of the generated synthetic MRIs. We also evaluated the ability of diffusion models to conditionally sample MRI brains using a 3D CNN-based disease classifier relative to real MRIs. In our experiments, the diffusion models generated synthetic data that helped to train an AD classifier (using only 500 real MRI scans) - and boosted its performance by over 3% when tested on real MRI scans. Further, we used classifier-free guidance to alter the conditioning of an encoded individual scan to its counterfactual (representing a healthy subject of the same age and sex) while preserving subject-specific image details. From this counterfactual image (where the same person appears healthy), a personalized disease map was generated to identify possible disease effects on the brain. Our approach efficiently generates realistic and diverse synthetic data, and may create interpretable AI-based maps for neuroscience research and clinical diagnostic applications.